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The Regulatory Imperative International Perspective Termis

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									          World Congress
Tissue Engineering and Regenerative
    Medicine International Society
                       Vienna, Austria
                     September 5-8, 2012


          Industry Day Symposium
                       SESSION 2:
 “The Regulatory Imperative: International Perspective”


                               Organized by
                               TERMIS-AM and TERMIS-EU
                               Industry Committees
            Concept/Discovery Research
              to Successful Product

                            Public/Private
                            Funding



Discovery
                   Clinical Trials                  Market           Successful Product
Research




             Intellectual Property           Regulatory Evaluation      Public(s) Perception
              & Patent Protection              & Product Approval      & Market Acceptance



                                      SCIENCE
                                     Talent/People
                                                                                               2
TERMIS-EU Industry Committee
• Established 2011
• Mission
   – Motivate translation of academic research into commercial products,
     in Tissue Engineering/Regenerative Medicine (TE/RM)
   – Connect the scientific & clinical communities with TE/RM industries
• Goals
   – Give answers to critical questions, paving the road of TE/RM
     commercial translation, by key stakeholders, from past experiences
   – Promote academia–industry meetings & partnerships for more
     effective commercial translation in TE/RM
• Members
   –   Yves Bayon, PhD; Covidien – Sofradim Production; Chair
   –   Simon Ellison, MBA; NHS Blood & Transplant
   –   John Barry, PhD; Baxter Innovations
   –   Paul Stroemer, PhD, Reneuron
   –   Chris Mason, PhD; University College of London
                                                                    3
   –   Alain Vertes, PhD; London Business School Sloan Fellow
        TERMIS-AM Industry Committee
• Established 2009
• Mission
   – Support commercialization in Tissue Engineering/Regenerative
     Medicine (TE/RM)
• Goals
   – Define and address obstacles/hurdles to product
     commercialization
   – Promote collaborations to build a viable TE/RM industry
• Members
   –   Kiki B. Hellman, PhD; The Hellman Group. LLC; Chair
   –   Timothy A. Bertram, DVM, PhD; Tengion
   –   Peter C. Johnson, MD; Avery Dennison
   –   Mark Van Dyke, PhD; Wake Forest University Health Sciences
   –   Bill Tawil, PhD; Baxter Biosurgery


                                                                    4
           TERMIS-AM Industry Committee
            ‘Commercialization Hurdles’
2010 – First Annual Industry Committee Symposium*
• Survey of TERMIS-AM membership on perceived
  hurdles to commercialization of TE/RM products
• Most common hurdles identified by academe, and start-
  up, development stage, established companies
        – Funding
        – Regulatory pathway
        – IP and technology transfer
-----
*Publications:
1. “Hurdles in Tissue Engineering/Regenerative Medicine Commercialization: A Survey of North
   American Academe and Industry,” Tissue Engineering, January 2011.
2. “Challenges in Tissue Engineering and Regenerative Medicine Product Commercialization: Building
   an Industry,” Tissue Engineering, January 2011.
                                                                                                 5
          TERMIS-AM Industry Committee
                   ‘Funding’
2011 – Second Annual Symposium*
• Survey of financial community (public, private,
  government)
• Key Findings
       – Investment interest >60%
       – Perceived challenges for investment
          • Regulatory pathway clarity
          • Clinical translation

 ---
 Publication:
 “Hurdles in Tissue Engineering/Regenerative Medicine Commercialization: A Survey of the
 Financial Industry,” Tissue Engineering, November 2012 (in press).
                                                                                           6
   The Regulatory Imperative:
    International Perspective
TERMIS-NA Industry Committee Surveys

   Regulatory pathway a major hurdle

 Regulatory clarity and predictability –
    key for commercialization and
       industrial development


                                           7
     The Regulatory Imperative:
      International Perspective
                 Regulatory Framework
 Principles and requirements governing assessment of regenerative
            products, i.e., review and marketing approval

                         Globalization
 Challenges for regulatory authorities due to the global R&D effort in
       TE/RM outside their purview, i.e., outside US and EU

               Regulatory Harmonization
Development of a common dialogue and approach among regulatory
authorities leading to congruence of national practices and consensus
   on regulatory requirements, i.e., a unified regulatory strategy


                                                                         8
      Symposium Participants
                           Presentations
 Lucia D’Apote, PhD; European Medicines Agency (EMEA), United Kingdom
Celia Witten, MD, PhD; Center for Biologics Evaluation and Research (CBER),
              Food and Drug Administration (FDA), United States

                                 Panel
               Tim Bertram, DVM, PhD; Tengion, Inc., USA
                  Maria Pascual-Martinez, PhD; TiGenix
                     Alison Wilson; Cell Data Services
                       Leslie Wolfe, PhD; Genzyme

                                 Chair
           Kiki B. Hellman, PhD; The Hellman Group, LLC, USA

                              Summary
               Tim Bertram, DVM, PhD; Tengion, Inc., USA

                                                                              9
European Regulatory environment of
regenerative medicine


TERMIS Industry Symposium
7 September 2012, Vienna (Austria)



Presented by: Lucia D’Apote, PhD     An agency of the European Union
European Medicines Agency
                           Overview


    The EMA CAT and the RegMed pipeline in Europe
     Regulatory path and regulatory requirements
                         Specificities and Challenges
                            International
                            Cooperation (EMA-FDA)


11 Lucia D’Apote - EMA
    The EMA CAT and the RegMed pipeline in Europe




12 Lucia D’Apote - EMA
                           Established in 1993, operational since 1995




                                                           7 Westferry Circus
                                                            Canary Wharf
                                                            London E14 4HB
                                                            United Kingdom

                                                        Tel:+44 (0) 20 7418 8400
                                                        Fax: +44 (0) 20 7418 8416
13   Lucia D'Apote - EMA
                                                        www.ema.europa.eu
                           The ATMP Regulation


     Committee for Advanced Therapy


      New Scientific Arena
       Expertise
         Beyond Traditional
           Research
14   Lucia D'Apote - EMA
                     ATMP Pipeline – what we see




15   Lucia D'Apote - EMA
Objective : Facilitate development of ATMPs
        and access to MA procedure
      ► understand  trends in research and development, with a view
       to planning CAT workload and resources accordingly




                                                 http://www.ema.europa.eu/doc
                                                 s/en_GB/document_library/Wor
                                                 k_programme/2010/11/WC500
 16                                              099029.pdf
                ATMP Pipeline – what we will see




► 318 clinical trials from EudraCT (1 May 2004 - 31 December
  2010)
► 244 national = more than 70%
► 74 multinational = less than 30%

17   Lucia D'Apote - EMA
                               Products

Based on self-classification:
► GTMPs + sCTMPs + TEPs: 250
► GTMPs =54 = 22%
► sCTMP/TEPs= 196 = 78%




►    phase I and II or I/II: 81%
►    phase III/IV:19%
►    phase IV, as assigned in the database: 7 CT
18
                         Sponsors: who



► Who    is conducting the CT with
     ATMPs in Europe? 173 sponsors


104=60% Academia/hospitals,
69=40% Industry (including SMEs)
4% big pharma
24% SMEs
72% other (non registered SMEs)



19
                Sponsors: from where

► 19 countries in total
► 15 EU/EFTA Countries (SP, DE, UK, NL, FR, BE)
► 4 non-EU/ EFTA region (US, Israel, Switzerland, Canada)
► almost all academia/charity sponsors situated in Europe
► some commercial sponsors (24/69 or 34%) situated outside Europe




20
                           Therapeutic areas

     majority of CT in solid tumours (67 products), followed by the
     cardiovascular area (48 products), and haematology including
     haematological malignancies (33 products)




21   Lucia D'Apote - EMA
                           Orphan ATMPs
                                  26 CT with Orphan
                                    ATMPs
                                  Mainly commercial
                                   sponsors
                                  Majority with cell-
                                   based products


                                  75 ODD so far are
                                    ATMPs !!!
22   Lucia D'Apote - EMA
          Regulatory path and regulatory requirements




23 Lucia D’Apote - EMA
     EU Marketing Authorisation (MA) for
     ATMPs

     A medicinal product may only be placed on the market
     in the EU,
     when a marketing authorisation has been issued
     by the European Commission
     (via the Centralised Procedure – EMA)
     or
     it is regulated by the competent authority of a EU Member
     State
     (hospital exemption)

24   EMA - Lucia D'APOTE
                                                             24
25   Lucia D'Apote - EMA
Risk based approach




26   Lucia D'Apote - EMA
Risk-management plan and follow-up
safety/efficacy




27   Lucia D'Apote - EMA
Same evaluation, different MA?

• Conditional approval vs Exceptional circumstances
- to meet unmet medical needs of patients and in the interest of
public health




28   Lucia D'Apote - EMA
Accellerated assessment 150 days
- in order to meet, in particular the legitimate expectations of
  patients and to take account of the increasingly rapid progress
  of science and therapies, for medicinal products of major
  interest from the point of view of public health and in
  particular from the view point of therapeutic innovation.
- There is no single definition of what constitutes major public
  health interest. This should be justified by the applicant on a
  case-by-case basis.




29   Lucia D'Apote - EMA
                         Specificities and Challenges



30 Lucia D’Apote - EMA
        ATMP Translation: perceived challenges


                         Gene and Cell based products are complex
                          Market (specific and small)
                            Lack of funds and costly investments
                                Regulatory barriers

31 Lucia D’Apote - EMA
Challenges with ATMPs: examples
• Scientific challenges
     – Manufacturing constraints & quality issues
     – Non-clinical challenges
     – Clinical challenges



            Disclaimer: ATMPs are a very diverse group of products,
          so the challenges listed in the next slides are only examples!




32
Quality/manufacturing issues

     -   Control of all starting and raw materials

         -    Human cells/tissues + any human/animal reagents (e.g serum)

         -    Recombinant growth factors

         -    History of cell-lines / vector constructs

     -   Appropriate characterisation and product testing (including potency assay*)

         -    Poor definition and control of a product may directly effect safety & efficacy

         -    Good control of the product is essential for manufacturing changes (e.g. product
              upscale)

     -   Manufacture in GMP environment


     *   Potency assay: product specific, at least semi-quantitative, linking product testing with clinical effect
33
         /biological activity
Non-clinical challenges
     – What animal models to be used to test a human cell-based
       therapy or gene therapy product?
       – Use of a homologous model? / Disease models?/ Other
         relevant animal models?
       – Proof of concept studies / toxicity studies
     – Dose finding studies?
     – Bio-distribution studies?
       – Germ line transmission for GTMP
       – Environmental risk / Shedding studies for GTMP


34
Clinical challenges
     – Dose finding studies
        – How to find the most effective dose, e.g. for a TEP?
     – Design of clinical trial
        – What is a suitable compatitor?
        – Blinding might be very difficult
        – Endpoints for TEP (how to measure structure repair?)
        – Effect of concomitment treatment / surgery on Efficacy &
          Safety?
     – Long term efficacy and safety follow-up studies

35
Challenges with ATMPs
• Scientific challenges
     – Yes!

• But not all challenges are scientific!
     – Regulatory issues
       – Lack of regulatory expertise
       – Resources
     – Reimbursement issues
     – Competition with ‘hospital exempted ATMPs’

36
Prospective product development




                            Courtesy of dr. Paula Salmikangas, 2012
37   Lucia D'Apote - EMA
Retrospective product development




                            Courtesy of dr. Paula Salmikangas, 2012

38   Lucia D'Apote - EMA
                         The way forward


   Raise awareness – strengthen dialogue
   Learn from experience




39 Lucia D’Apote - EMA
                         Nature Reviews Drug
                         Discovery, vol 9,
                         March 2010, 185-201




Regulatory Rapporteur,
vol 8, July-August
2011, 4-7



40
                           Advice during development




41   Lucia D'Apote - EMA
                   Regulatory strategy: save time
     Scientific advice: Complying with SA/PA is significantly
     associated with positive outcome

                                     Positive MAA outcome related to compliance with SA/PA
                                                           received



                              100%

                              90%
                                                 97%
                              80%

                              70%               38/39
                                                                                             72%
                              60%

                              50%                                                          93/129
                              40%

                              30%
                                                                      30%
                              20%

                              10%                                      6/20
                               0%
                                       Compliant with SA   Non-compliant with SA    No SA received
                                                                 received

                   Regnstrom J, Koenig F, Aronsson B, et al. (2010) Factors associated with success of market authorisation
                      applications for pharmaceutical drugs submitted to the European Medicines Agency; EJCP 66:39-48

42   Lucia D'Apote - EMA
43 Lucia D’Apote - EMA
44 Lucia D’Apote - EMA
                 International Cooperation (EMA-FDA)


FDA-EMA-HC ATMP Cluster
ICH Regulators Forum Cell Therapy Group
Parallel Scientific advice

  http://www.ema.europa.eu/docs/en_GB/document_libra
  ry/Other/2009/11/WC500014868.pdf




45 Lucia D’Apote - EMA
Parallel Advice FDA
Confidentiality Agreement FDA
Applicant to address request to both Agencies
Agreement principles since 2004 pilot
Applicant initiative- exceptionally Agency initiative




46
Procedure Parallel Advice
Initial discussion both Agencies
Prime candidates-breakthrough products – no GL
  exist or GLs differ between Agencies
Submit request in usual manner
Timetable agreed between Agencies
Tele-video-conference about D60



47
Outcome
No applicant involvement in draft reports
Parallel separate advice given not ‘joint’ advice
Confidentiality maintained
Standard fee applies




48
                Thank you for your attention!




                                         Lucia D’APOTE
                               European Medicines Agency (EMA)
                                 lucia.dapote@ema.europa.eu

49   Lucia D'Apote - EMA
Regulatory and Scientific Experience
in Regenerative Medicine in OCTGT

       Termis Industry Symposium
             Vienna, Austria
           September 7, 2012
                 Celia M. Witten, PhD, MD
                       Office Director
      Office of Cellular, Tissue, and Gene Therapies
      Center for Biologics Evaluation and Research
       United States Food and Drug Administration
Outline
• FDA Mission & Organization
• OCTGT Activities
• Special Programs




                               2
                        51
FDA Mission Statement
 The FDA is responsible for protecting the public health
  by assuring the safety, efficacy, and security of
  human and veterinary drugs, biological products,
  medical devices, our nation’s food supply, cosmetics,
  and products that emit radiation.
 The FDA is also responsible for advancing the public
  health by helping to speed innovations that make
  medicines and foods more effective, safer, and more
  affordable; and helping the public get the accurate,
  science-based information they need to use
  medicines and foods to improve their health.

                           52                             3
FDA Organization
• CBER (Center for Biologics Evaluation and Research): vaccines,
  blood and blood products, human tissue/tissue products for
  transplantation, cells, gene therapy
    – Office of Cellular, Tissue, and Gene Therapies
    – Office of Vaccines Research and Review         Product Offices
    – Office of Blood Research and Review
• CDER (Center for Drug Evaluation and Research): drugs, some
  biological products
• CDRH (Center for Devices and Radiological Health): devices for
  treatment, implants, diagnostic devices
• CVM
• CFSAN
• NCTR
• CTP
• ORA
• OC

                                                                       4
OCTGT Activities
•   Regulatory review
•   Policy and regulatory guidance development
•   International Activities and Standards
•   Outreach
    – Advisory Committees
    – Talks, workshops
    – Seminars, panel discussions, round table
• Publications
• Mission-related Research

                                                 5
New IND and IDEs Submitted to OCTGT:
Commercial or Research Sponsors


  140
  120

  100
   80
                                                       commercial
   60                                                  research
   40
   20
   0
        2003 2004 2005 2006 2007 2008 2009 2010 2011



                                                               6
Examples of OCTGT Products
•   Stem cell and stem cell-derived products
     – Hematopoietic, mesenchymal, cord blood, embryonic, iPSc, etc
•   Somatic cell therapies
     – Pancreatic islets, chondrocytes, myoblasts, keratinocytes, hepatocytes
•   Gene therapies
     – Genetically modified cells
     – Plasmids, viral vectors, bacterial vectors
•   Therapeutic vaccines and other antigen-specific active immunotherapies
     – Cancer vaccines and immunotherapies, such as dendritic cells,
       lymphocyte-based therapies, cancer cell-based therapies, peptides,
       proteins
     – Non-infectious disease therapeutic vaccines, such as peptides, proteins,
       small molecules
•   Devices and combination products
     – Devices with a cellular component
     – Selected devices for the manufacture or delivery of cells



                                                                             7
Regulatory
 Review


             8
FDA Medical Product Regulatory
Paradigms are Tiered
•   Risks Inherent to the Product
•   Manufacturing Complexity
•   Clinical Uses
•   Other Differences

     Leads to Tiered Review Requirements


                                           9
Two General Classes of
FDA-Regulated Medical Products
• No Premarket Review
  – Some Human Tissues (361 HCT/Ps)
  – Some Devices (exempt 510(k))
  – Some Drugs (monograph)

• Premarket Review/notification
  –   510(K) Devices (non-exempt)
  –   PMA Devices
  –   BLA- Biologic Drugs
  –   NDA- Drugs

                                      10
Starting Point for FDA Interaction
• Guidance in specific investigational areas
   – Preparation of IDEs and INDs for Products Intended to Repair or
     Replace Knee Cartilage
   – Somatic Cell Therapy for Cardiac Disease
• General guidances to support specific areas of tissue
  engineered medical products
   –   CMC guidances for cellular and gene therapy products
   –   General preclinical guidances
   –   Guidances for scaffolds and devices
   –   General clinical guidances
• Standards from SDOs (ASTM, ICH, ISO, USP...)

• Pre-submission meeting with appropriate FDA
  Center/office

                                                                   11
Policy & Regulatory
    Guidance
  Development


                      12
Recent CBER Guidances
   Guidance for Industry: Cellular Therapy for Cardiac Disease (Oct 2010)
   Guidance for Industry: Potency Tests for Cellular and Gene Therapy
    Products (Jan 2011)

   Guidance for Industry: INDs for Minimally Manipulated, Unrelated
    Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic
    Reconstitution for Specified Indications (June 2011)

   Guidance for Industry: Clinical Considerations for Therapeutic Cancer
    Vaccines (Oct 2011)

   Current Good Tissue Practices (CGTPs) for Manufacturers of Human
    Cells, Tissue and Cellular and Tissue-Based Products (HCT/Ps)
             (Dec 2011)

   Preparation of IDEs and INDs for Products Intended to Repair or Replace
    Knee Cartilage (Dec 2011)


                                                                             13
FY 2012 Program Priorities

Guidance for Industry:

Draft – Preclinical Safety Assessment
of Investigational Cellular and Gene
Therapy Products



                                        14
Recent CTGTAC Advisory Committee Topics

  Testing for Replication Competent Retrovirus (RCR) Lentivirus
   (RCL) in Retroviral and Lentiviral Vector Based Gene Therapy
   Trials – November 2010

  Cell and Gene Therapy Trials in Retinal Disease – June 2011

  New York Blood Center BLA for umbilical cord blood -
   September 2011

  Miltenyi Biotec HDE for CliniMACS CD34 Selection System –
   September 2011

  Organogenesis BLA for the treatment of surgically created
   gingival and alveolar mucosal surface defects in adults –
   November 2011


                                                                   15
International Activities
    and Standards




                           16
FDA’s Goals for International
Collaborations
• To safeguard global public health,
• To assure that consumer protection standards
  and requirements are met,
• To facilitate the availability of safe and effective
  products,
• To develop and utilize product standards and
  other requirements more effectively
• To minimize or eliminate inconsistent standards
  internationally.
                                                         17
FDA-European Medicines Agency (EMA)-
Health Canada (HC) ATMP Cluster
• Regular teleconferences to share thinking
  on regulatory approaches on both general
  and specific issues
• Share draft documents for comments
• Engage reciprocally in workshops advisory
  committees, and working parties



                                          18
Asia Pacific Economic Cooperation-Life
Sciences Innovation Forum (APEC/LSIF)
• 13 countries participated
• Goal: To bring together a group of stem cell leaders
  from corporate, academic, and government sectors to
  discuss and further develop a regulatory frame work for
  QA/QC for stem cell products
• Information Gathering Opportunities
   – Regulatory landscape for cell therapies
   – Guidance documents in place or under development for (stem)
     cell therapies
   – (Stem) cell therapy products in clinical trials or already licensed
• Outcomes: Regulatory gaps for stem cell products exist
  among the participating countries


                                                                           19
Regulators Forum Cell Therapy Group
 • Goal: Identify areas of possible areas for
   convergence/harmonization
 • Why convergence/harmonization for cell therapy
   products?
 • Cell therapy is an emerging product class posing
   substantial regulatory challenges
 • Regulatory frameworks are in different states of maturity
   internationally
 • Limited experience in reviewing marketing applications
   for cell therapy products
 • ICH & non-ICH product guidelines not directly applicable
   to CT products
 • Harmonization of technical requirements useful tool to
   strengthen the safe and effective use of cell (stem)-
   based products
                                                           20
Regulations vs. Standards
• Regulations
  – Government implementation of statues that have the force of law
  – Define specific requirements for safety
  – Provide accurate information to health professionals and
    consumers
• Standards
  – Voluntary
  – Frequently developed outside of the government
  – Written standards describe how manufacturers might meet
    regulatory requirements
  – Physical standards provide accepted “benchmark” materials



                                                                 21
Use of Consensus Standards by
Federal Agencies

• Mandated by PL 104-113 National Technology
  Transfer and Advancement Act of 1995

• Interpreted by OMB Circular No. A119
  http://www.whitehouse.gov/omb/circulars_a119_a119fr

• Standards and Global Harmonization




                                                        22
Impact of Guidance and Standards
• SDOs can sometimes produce documents or
  physical standards more quickly than FDA can
  produce Guidance documents
• Effort can be shared with non-FDA experts
• SDOs can cover areas that are difficult to put in
  FDA Guidance
   – Specific (proprietary) methods for tests or
     processes
   – Critical reviews of emerging fields

                                                      23
Use of Standards in CBER
• Use in Review of Applications
  – Sponsor cites standard in meeting or application
     • ISO 10993.xx (Biocompatibility)
     • ATCC VR-1516 (Adenovirus Type 5 Reference Material)
  – Use as Information Resource
     • ASTM 2451-05 – Standard Guide for in vivo assessment of
       implantable devices intended to repair or regenerate articular
       cartilage
     • ANSI/AAMIISO 7198 Cardiovascular Implants: Vascular
       Graft Prostheses




                                                                   24
International Clinical Trials
• Acceptance of studies in support of an IND
  or marketing application
  – If conducted under an IND all requirements
    must be met unless waived
  – If not conducted under an IND must meet
    21CFR312.120, which addresses good
    clinical practice issues, ability to validate data
    from onsite inspection if necessary,
    supporting information, etc.

                                                     25
International Clinical Trials
• Acceptance of foreign data as sole basis
  for marketing approval is governed by
  21CFR312.120
  – Applicability of data to u.s. population and
    medical practice
  – Studies performed by clinical investigators of
    recognized competence
  – Data valid without an onsite inspection or FDA
    can perform on-site inspection to validate data

                                                 26
Special Programs




                   27
Fast Track, Accelerated
Approval, and Priority Review
• These terms apply to licensure or to the licensure
  process for drugs and biologics
• Fast Track: process designed to facilitate the
  development, and expedite the review of drugs to treat
  serious diseases and fill an unmet medical need
• Accelerated Approval: allows earlier approval of drugs
  to treat serious diseases, and that fill an unmet medical
  need based on a surrogate endpoint. A confirmatory trial
  is needed.
• Priority Review: Two tiered system of review times
   – Standard Review: ten month time frame
   – Priority Review: six month time frame. Designation is given to
     drugs that offer major advances in treatment, or provide a
     treatment where no adequate therapy exists.

                                                                      28
Expanding Access to Investigational Drugs
 • Use of an investigational drug outside of a
   clinical trial, for the sole purpose of treating a
   patient or patients with a serious or life-
   threatening disease who have no acceptable
   medical options
 • Levels of expanded access are based on the
   number of patients to be treated and how much
   is already known about the drug:
    – Individual or intermediate size group access
    – Treatment IND


                                                        29
Orphan Drug and Humanitarian
Device Designation
• Orphan Drug Designation: orphan status to drugs and
  biologics which are defined as those intended for the
  safe and effective treatment, diagnosis or prevention of
  rare diseases/disorders that affect fewer than 200,000
  people in the U.S., or that affect more than 200,000
  persons but are not expected to recover the costs of
  developing and marketing a treatment drug
   – This does not alter the standard regulatory requirements and
     process for obtaining marketing approval
• Humanitarian Use Device: designates a device that is
  intended to benefit patients by treating or diagnosing a
  disease or condition that affects fewer than 4,000
  individuals in the United States per year
   – HDE exemption

                                                                    30
Food and Drug Administration Safety
and Innovation Act (FDASIA)
• Signed into law July 9, 2012
• Fifth reauthorization of PDUFA
• Sec 902- Breakthrough Therapies
   – Criteria for “Breakthrough Therapy” Designation
   – Potential agency actions to expedite review of
      designated drugs
   – Guidance document on implementation by 18 months




                                                    31
OCTGT Regulatory Resources
• OCTGT Learn Webinar Series:
  http://www.fda.gov/BiologicsBloodVaccine
  s/NewsEvents/ucm232821.htm

• Regulatory Questions:
  CBEROCTGTRMS@fda.hhs.gov
  Patrick Riggins, Ph.D. – (301)827-6536


                                           32
                               81
Public Access to CBER
  CBER website:
  http://www.fda.gov/BiologicsBloodVaccines/default.htm

  Phone: 1-800-835-4709 or 301-827-1800

  Consumer Affairs Branch (CAB)
  Email: ocod@fda.hhs.gov
  Phone: 301-827-3821

  Manufacturers Assistance and Technical Training Branch
  (MATTB)
  Email: industry.biologics@fda.gov
  Phone: 301-827-4081

  Follow us on Twitter
  https://www.twitter.com/fdacber
                                                           33
Contact Information
Celia Witten, Ph.D., M.D.
Office Director, OCTGT
CBER/FDA
1401 Rockville Pike (HFM-700)
Rockville, MD 20852-1448
301-827-4163
celia.witten@fda.hhs.gov

                                34
           Panel Discussion
                    Question #1
– Since product development, including clinical studies
  in TE/RM is now a global enterprise, what CMC,
  clinical, and pharmacology/toxicology aspects of
  international studies may be acceptable to both
  EMEA and FDA?
– What criteria will form the basis for regulatory
  decision-making in product approval?




                                                          84
           Panel Discussion
                    Question #2
– What priorities do the FDA and EMEA foresee in
  developing ‘best practices’ for regenerative products,
  i.e., clinical trial design, manufacturing processes and
  release criteria, among others?
– How can ‘best practices’ from various regulatory
  agencies be developed and adopted to accommodate
  reciprocity across national boundaries?
– What industrial-regulatory mechanisms are the most
  effective in establishing a cooperative dialogue with
  FDA and EMEA regarding such issues?
                                                          85
          Panel Discussion
                   Question #3
The FDA and EMEA have different legislated product
approval pathways permitting accelerated or expedited
product approval.
– What criteria would form the basis for accelerated or
  expedited product review of a TE/RM product?
– Would any other means of rapid product approval for
  TE/RM products be considered as long as patient
  safety is demonstrated?



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Regulatory Imperative Session Summary

• Regulatory barriers are considered as major challenges for TE/RM
  product commercialization - academics, industrialists, financiers,
  and regulators.
• Both FDA and EMA have recognized the regulatory challenges
  presented by TE/RM product technologies, raw materials, pre-
  clinical testing, and clinical assessment.
• TE/RM product pipeline is broad and deep presenting unique
  challenges for regulators such that the EMA CAT and FDA Pre-
  Submission Meetings allow sponsors to obtain specific guidance on
  their respective technology (cells, genes, combinations, etc).
• TE/RM products are complex presenting unique manufacturing, pre-
  /non-clinical and clinical challenges for regulation




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    Regulatory Imperative Session Summary
•   Both EMA and FDA:
    – Take a risk-based/tiered approaches to evaluate the specific risks unique
    to each TE/RM product submission.
    – Have identified special pathways (e.g. orphan, accelerated assessments,
    etc) to encourage TE/RM therapies reaching the market most expeditiously
    and are safe and effective for the intended patient population.
    – Promote long-term follow-up on safety, efficacy and durability of TE/RM
    products
    – Have entered into agreement for parallel advice and collaborations with
    industrial organizations on regulation of TE/RM product development
    – Offer specific guidance to industry in key technological areas of concern:
    scientific advise being sought by sponsors has focused on non-clinical
    challenges although clinical trial design have also served as a topic of
    industrial interest.
    – Accept international studies for marketing applications if they meet
    specific requirements for data validity, good clinical practices and
    supporting information
                                                                                   88
 Regulatory Imperative Session Summary
• The way forward for TE/RM technologies and products includes:
   – Raise awareness of unique safety challenges and efficacy
   opportunities
   – Learn from experience as these new technologies advance to
   commercialization and become standards of care.
   – Promoting industrial-regulatory and regulatory-regulatory dialog
   to promote the commercialization of safe and effective TE/RM
   technologies for unmet medical needs




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     A copy of the slides for
Session 2 will be available online
    via the TERMIS website,
         www.termis.org.




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